Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/30—Zinc; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
  • A61K8/27—Zinc; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
  • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/004—Aftersun preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations

Definitions

• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a chromene derivative and bivalent zinc as well as the use of the said active ingredients for the making of medicaments effective against dermatoses and for cosmetic purposes.
• chromene derivatives have been employed in the oral treatment of allergic asthma and rhinitis.
• the probably best known compound in this field is cromoglycinic acid.
• structurally related chromene compounds have been synthesized and partly introduced in therapy of allergic disorders, such chromenes are e.g. minocromil, nedocromil, terbucromil, proxicromil, ambicromil, isocromil and others.
• compositions for topical treatment of atopic eczema are not very effective for all degrees of atopic eczema, including severe atopic eczema and they are effective only after a prolonged period of treatment.
• Zinc acetate has been found useful to influence favourably the effects of the macrolide antibiotic erythromycine in topical compositions for the treatment of acne (Zineryt - trademark of Roehm Pharma GmbH, Darmstadt). The application of such antibiotic substance is not always desirable subject to allergic reactions against the same, in cases of pregnancy etc..
• an object of the present invention is to provide an effective composition which is useful for the treatment of all degrees of dermatoses, including severe atopic eczema, and also for cosmetic purposes and which is effective after a short period of treatment.
• the composition shall be free of antibiotics or hormone substances.
• compositions comprising a pharmaceutically effective amount of bivalent zinc in combination with at least one chromene derivative of the general formula where m, n, o, X, R1 to R10 have the following meanings: m an integer from 0 to 2 n an integer from 1 to 2 o an integer from 0 to 1 X is a carboxyl group or a phenyl radical which is optionally substituted by an alkyl group, having from 1 to 4 C atoms R1 is hydrogen, a hydroxyl group or an optionally substituted radical having the general formula where m and n have the meaning above and R9 is a hydrogen atom, a hydroxyl group or an alkyl radical having from 1 to 4 C atoms, R10 is a hydrogen atom, an alkyl radical with 1 to 4 C atoms or a phenyl radical which is optionally substituted 1 to 3 times by an alkyl radical, a hydroxyl group or an aliphatic
• the chromene derivative which is especially preferred in this invention is cromoglycinic acid and the pharmaceutically active salts, lower alkyl esters (C1-C10, particularly C1-C4) or amides which may be alkylated by C1-C4-alkyl thereof.
• the pharmaceutically preferred salts the alkali metal and alkaline earth metal salts can be mentioned.
• the zinc salts of cromoglycinic acid and, in a broader aspect, of the respective chromene derivative may be mentioned.
• the alkali metal when employed in the present invention is not critical thereto and can be any pharmaceutically acceptable alkali metal such as sodium, potassium, lithium, rubidium or combinations thereof.
• Sodium is the preferred alkali metal.
• the alkaline earth metal when employed in the present invention is not critical thereto and can be any pharmaceutically acceptable alkaline earth metal such as calcium or magnesium. Magnesium is the preferred alkaline earth metal.
• the amount of the chromene derivative is in a pharmaceutically or cosmetically effective amount which in general is from about 1% to about 25%, preferably from about 2% to about 10% by weight based on the total weight of the composition.
• bivalent zinc employed in the present invention is not critical thereto and can be in the form of bivalent zinc compounds such as zinc oxide, zinc lactate, zinc chloride, zinc carbonate, zinc sulfate, zinc acetate or combinations thereof.
• Zinc oxide is the preferred form of bivalent zinc employed in the present invention because it has a white colour and easily masks the skin well.
• pharmaceutically acceptable buffering agents can also be employed to adjust the pH to about physiological levels, i.e. about pH 5.0 to 7.7.
• the bivalent zinc is also employed in an effective amount ranging from about 1% to 25%, preferably from about 4% to about 10% by weight of bivalent zinc compound based on the total weight of the composition.
• the composition of this invention is highly effective in the treatment of skin disorders at mammals (cats, horses, dogs) and particularly man at any degree. Normally the composition will be applied as a pharmaceutical but also cosmetic applications may be possible.
• the skin disorders which can be successfully treated are dermatoses and these comprise particularly eczema including atopic eczema, psoriasis, dermatitic disorders due to allergic reaction (e.g. antibiotic, metals like Ni, organic chemicals), ulcers including colitis ulcerosa, urticaria, inflammatory skin conditions, e.g. due to Crohn's disease and others.
• the cosmetic applications may have to do with treatment of acne, of wrinkles and of sun burns etc..
• compositions of this invention are normally applied in topic administration. Such topical applications can be in form of solution, emulsion, suspension, ointment, cream, gel, lotion or spray. The use of emulsions, gels and ointments is generally preferred.
• topical compositions can be made using known techniques in the art for the making of such compositions. While topical composition of varying nature as above can be utilized, often the use of an oil-in-water or water-in-oil emulsion are preferred.
• the oil of the oil phase can be any pharmaceutically acceptable oil such as a vegetable oil, e.g. olive oil, soybean oil, jojoba oil, coconut oil, avocado oil, etc., an animal oil such as whale oil and mink oil, etc., or combinations thereof.
• Olive oil is the preferred oil because it is non-allergenic.
• the water of the water phase may be any pharmaceutically acceptable water such as sterile water, deionized water, double distilled water or tap water. Double distilled water is the preferred water because of the high degree of purity thereof.
• additives such as preservatives, emulsifiers, emollients, biologically active substances such as naturally occurring flavonoides, sun screens, colorants, fragrances or other additives typically employed in topical compositions can be added to the composition of the present invention.
• preservatives examples include para-benzoic acid, sorbic acid and tocopherols.
• Para-benzoic acid can be added in an amount of from about 0.5 to 3%, preferably from about 1% to about 1.5% by weight based on the total weight of the composition.
• Sorbic acid can be added in an amount of from about 0.05 to 0.1% by weight based on the total weight of the composition.
• Tocopherols can be added in an amount of from about 0.1 to 0.2% by weight based on the total weight of the composition.
• the preservatives are added to the water phase. For solutions, sprays and lotions the use of pharmaceutically acceptable chelates and particularly EDTA has been found useful for additional stabilization.
• emulsifiers which can be employed in the present invention include cetylstearyl alcohol, cetylstearyl sulfonate, eucerin, Eucerit, Emulgol (L. Givaudan & Co.), Emulgators 8077 and 8092 (Dragoco GmbH) and Emulgator oil/water (Ciba Geigy) or combinations thereof. Additional examples of emulsifiers which can be employed in the present invention are described in Kirk-Othmer Encyclopaedia of Chemical Technology 3rd Ed. (John Wiley & Sons,1979, Vol. 7, pages 146-148), which is incorporated by reference herein.
• the emulsifiers can be added in an amount of from about 10% to 20%, preferably from about 12% to 15% by weight based on the total weight of the composition. Generally, the emulsifiers are added to the oil phase.
• emollients which can be employed in the present invention include wool wax, lecithin, cholesterin, eucerin, Eucerit and neatsfoot oil or combinations thereof.
• the emollients can be added in an amount of from about 1.0% to 10%, preferably from about 3.0% to 5.0% by weight based on the total weight of the composition. Generally, the emollients are added to the oil phase.
• the sun screens can be added in an amount of from about 0.5% to about 6.0%, preferably from about 1.0% to 5.0% by weight based on the total weight of the composition. Generally, the sun screens are added to the oil phase.
• Colorants and fragrances as well as other additives can easily be added to the composition of the present invention in amounts conventionally employed as described in e.g. Kirk-Othmer Encyclopaedia of Chemical Technology 3rd Ed. (John Wiley & Sons,1979, Vol. 7, pages 143-176), which is incorporated by reference herein.
• Emulsions of the present invention can be produced by first preparing an oil phase containing a water-insoluble bivalent zinc compound, such as zinc oxide, and then preparing an aqueous phase containing the chromene derivative, e.g. an alkali metal or alkaline earth metal cromoglycate.
• Bivalent zinc oxide can also be added to the water phase instead of the oil phase if desired.
• the form of bivalent zinc is a water-soluble bivalent zinc compound, such as zinc chloride, it is added generally to the water phase.
• the oil phase is then mixed with the water phase to achieve an oil-in-water emulsion or the water phase is added to the oil phase to achieve a water-in-oil emulsion.
• the oil-in-water and water-in-oil emulsions can be prepared using conventional emulsification techniques such as a homogenizer, an emulsion mill and rollers.
• the particular size of the emulsion formed is not critical as long as the particle size is sufficient for the emulsion to be stable over a period of time.
• the temperature for preparing the oil phase will be above the melting point of the oil but not above the temperature at which the chromene compound and additives are degraded. Generally, the temperature is about 40°C to about 75°C.
• composition of this invention is generally applied to the skin in an amount of about 0.005 g to about 0.03 g per square centimeter of skin, preferably about 0.01 g to about 0.02 g per square centimeter of skin, although more or less can be employed as required by the patient's condition and the therapy desired.
• An oil phase containing the following components was prepared by admixing these components and melting such at 75°C. Thereafter, the water phase containing the following components was prepared by admixing these components at 40°C. Next, the oil phase was mixed with the water phase to prepare an oil-in-water emulsion.
• the resulting emulsion was employed to treat 14 adults ranging from 20-60 years of age (12 females and 5 males) and 3 children ranging from the age of 9-12 years (2 females and 1 male).
• composition of the present invention was topically administered twice a day (in the morning and in the evening) in an amount of about 0.015 g per square centimeter.
• one patient was excluded because the patient began taking corticoids (a member of group II) and another patient withdrew from the study because of dryness of the skin caused by application of the composition of the present invention (a member of group II).
• the patients recorded the day when they were free of itching, vesiculation and pruritus and were evaluated every two days for the degree of severity of eczema. From the 15 patients which finished the study, 7 were in group I and 8 were in group II at the time of first clinical assessment. Two of the 7 of group I were free of symptoms at the third day of administering the composition of the present invention. Of the other 13 patients, they were free of symptoms at the seventh day (8 patients) or the tenth day (5 patients). Of the 15 successfully treated patients, 4 needed no additional medication for weeks, 6 others administered the composition of the present invention occasionally to avoid excessive exacerbation and 5 administered the composition of the present invention routinely every day.
• the composition of the present invention is advantageous in that, due to the interaction of the alkali metal or alkaline earth metal cromoglycate and the bivalent zinc, it is effective in a shorter period of time than previous compositions employed for the treatment of atopic eczema and containing alkali metal or alkaline earth metal cromoglycate alone.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Birds (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Gerontology & Geriatric Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Cosmetics (AREA)

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Cited By (15)

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Citations (1)

• 1988
  • 1988-08-18 EP EP88113428A patent/EP0304802B1/de not_active Expired - Lifetime
  • 1988-08-18 DE DE88113428T patent/DE3879811T2/de not_active Expired - Fee Related
  • 1988-08-25 JP JP63211550A patent/JP2519988B2/ja not_active Expired - Fee Related

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